AALL0631: A Phase III Study of Risk Directed Therapy for Infants with ALL: Randomization of Highest Risk Infants to Intensive Chemotherapy +/- FLT3 Inhibition (CEP-701, Lestaurtinib; IND#76431)
| Type of Trial | Status of Trial | Age Range (yrs.) | Sponsor of Trial | Protocol ID |
|---|
| Treatment | Active | Under 1 at diagnosis | COG | AALL0631 |
Outline
Patients are stratified according to risk group (standard risk [MLL-G: germline or non-rearranged] vs intermediate risk [MLL-R: rearranged, age ≥ 90 days at diagnosis] vs high risk [MLL-R, age < 90 days at diagnosis]).
All patients receive induction therapy (weeks 1-3) comprising vincristine IV on days 1, 8, and 15; daunorubicin hydrochloride IV over 30 minutes on days 1 and 2; cyclophosphamide IV over 30 minutes every 12 hours on days 3 and 4; pegaspargase or asparaginase intramuscularly (IM) on day 4; oral prednisone or methylprednisolone IV three times daily on days 1-21; triple intrathecal (IT) chemotherapy comprising methotrexate, cytarabine, and hydrocortisone on days 1, 8, and 15; and filgrastim IV or subcutaneously (SC) beginning on day 5 and continuing until blood counts recover.
Standard risk patients are nonrandomly assigned to receive a less intensive chemotherapy regimen without lestaurtinib (post-induction therapy A).
· Post-induction therapy A (for standard-risk patients [MLL-G]):
· Induction intensification (weeks 4-7): Patients receive high-dose methotrexate IV continuously over 24 hours on days 22 and 29; triple IT chemotherapy on days 22 and 29; leucovorin calcium IV every 6 hours beginning 42 hours after start of high-dose methotrexate and continuing until methotrexate level is < 0.1 μM; cyclophosphamide IV over 30 minutes on days 36-40; etoposide IV over 2 hours on days 36-40; and filgrastim IV or SC beginning on day 41 and continuing until blood counts recover. Patients in morphologic remission proceed to re-induction therapy.
· Re-induction (weeks 8-10): Patients receive vincristine IV on days 1, 8, and 15; daunorubicin hydrochloride IV over 30 minutes on days 1 and 2; cyclophosphamide IV over 30 minutes every 12 hours on days 3 and 4; pegaspargase or asparaginase IM on day 4; dexamethasone IV or orally twice daily on days 1-7 and 15-21; triple IT chemotherapy on days 1 and 15; and filgrastim IV or SC beginning on day 5 and continuing until blood counts recover.
· Consolidation (weeks 11-17): Patients receive high-dose methotrexate IV continuously over 24 hours on days 1 and 8; leucovorin calcium IV every 6 hours beginning 42 hours after start of high-dose methotrexate and continuing until methotrexate level is < 0.1 μM; triple IT chemotherapy on day 1; etoposide IV over 2 hours on days 15-19; cyclophosphamide IV over 30 minutes on days 15-19; high-dose cytarabine IV over 3 hours every 12 hours on days 29 and 30; pegaspargase or asparaginase IM on day 30; and filgrastim IV or SC beginning on day 20 and day 31 and continuing until blood counts recover.
· Continuation I (weeks 18-39): Patients receive vincristine IV on day 1 in weeks 18, 22, 29, and 33; dexamethasone IV or orally twice daily on days 1-5 in weeks 18, 22, 29, and 33; triple IT chemotherapy on day 1 in weeks 18, 22, 29, and 33; methotrexate IV on day 1 in weeks 19-21, 23-35, 30-32, and 34-36; etoposide IV over 2 hours on day 1-5 in weeks 26 and 37; cyclophosphamide IV over 30 minutes on days 1-5 in weeks 26 and 37; oral mercaptopurine on days 1-7 in weeks 19-21, 23-35, 30-32, and 34-36; and filgrastim SC or IV beginning on day 6 in weeks 26 and 37 and continuing until blood counts recover.
· Continuation II (weeks 40-104): Patients receive vincristine IV on days 1, 29, and 57; dexamethasone IV or orally twice daily on days 1-5, 29-33, and 57-61; intrathecal methotrexate (IT MTX) on day 1; oral methotrexate on days 8, 15, 22, 36, 43, 50, 64, 71, and 78; and oral mercaptopurine on days 8-28, 36-56, and 64-84. Treatment repeats every 12 weeks for 2 years from diagnosis.
A safety/activity phase is conducted separately for the intermediate risk (IR) and high risk (HR) patients to identify a safe, tolerable, and biologically active dose of lestaurtinib combined with P9407-based chemotherapy backbone. Once a tolerable/active dose of lestaurtinib has been identified for IR patients, subsequent IR patients are eligible to proceed to an efficacy phase, where they are randomized to P9407- based chemotherapy backbone with or without lestaurtinib. HR patients separately proceed to the randomized efficacy phase if a tolerable/active dose is identified for the HR stratum. IR and HR patients are randomized to 1 of 2 post-induction therapy regimens (post-induction therapy B or C).
· Post-induction therapy B (chemotherapy only for IR/HR patients classified as MLL-R; age ≥ 90 days at diagnosis):
· Induction intensification (weeks 4-7): Patients receive high-dose methotrexate, leucovorin calcium, cyclophosphamide, etoposide, and filgrastim as in post-induction therapy A induction intensification. Patients in morphologic remission proceed to re-induction.
· Re-induction (weeks 8-10): Patients receive vincristine, daunorubicin hydrochloride, cyclophosphamide, pegaspargase or asparaginase, dexamethasone, triple IT chemotherapy, and filgrastim as in post-induction therapy A re-induction.
· Consolidation (weeks 11-17): Patients receive high-dose methotrexate, leucovorin calcium, triple IT chemotherapy, etoposide, cyclophosphamide, high-dose cytarabine, pegaspargase or asparaginase, and filgrastim as in post-induction therapy A consolidation.
· Continuation I (weeks 18-47): Patients receive vincristine on day 1 in weeks 18, 22, 31, 35, and 44; dexamethasone orally or IV twice daily on days 1-5 in weeks 18, 22, 31, 35, and 44; triple IT chemotherapy on day 1 in weeks 18, 22, 31, 35, and 44; methotrexate IV on day 1 in weeks 19-21, 23, 24, 32-34, 36, 37, and 45-47; oral mercaptopurine on days 1-7 in weeks 19-21, 23, 24, 32-34, 36, 37, and 45-47; etoposide IV over 2 hours on days 1-5 in weeks 25 and 38, high-dose cytarabine IV over 3 hours every 12 hours on days 1 and 2 in weeks 28 and 41; pegaspargase or asparaginase IM on day 2 in weeks 28 and 41; and filgrastim SC or IV beginning on day 6 in weeks 25 and 38 and beginning on day 3 in weeks 28 and 41 and continuing until blood counts recover.
· Continuation II (weeks 48-104): Patients receive vincristine, dexamethasone, IT methotrexate, oral methotrexate, and oral mercaptopurine as in post-induction therapy A continuation II. Treatment repeats every 12 weeks for 2 years from diagnosis.
· Post-induction therapy C (chemotherapy and lestaurtinib for IR/HR patients classified as MLL-R; age < 90 days at diagnosis):
· Induction intensification therapy (weeks 4-7): Patients receive high-dose methotrexate, leucovorin calcium, cyclophosphamide, etoposide, and filgrastim as in post-induction therapy B induction intensification. Patients also receive oral lestaurtinib twice daily on days 41-48. Patients in morphologic remission proceed to re-induction.
· Re-induction (weeks 8-10): Patients receive vincristine, daunorubicin hydrochloride, cyclophosphamide, pegaspargase or asparaginase, dexamethasone, triple IT chemotherapy, and filgrastim as in post-induction therapy B re-induction. Patients also receive oral lestaurtinib on days 5-20.
· Consolidation (weeks 11-17): Patients receive high-dose methotrexate, leucovorin calcium, triple IT chemotherapy, etoposide, cyclophosphamide, high-dose cytarabine, pegaspargase or asparaginase, and filgrastim as in post-induction therapy B consolidation. Patients also receive oral lestaurtinib on days 20-27 and 31-42.
· Continuation I (weeks 18-47): Patients receive vincristine, dexamethasone, triple IT chemotherapy, methotrexate, mercaptopurine, etoposide, high-dose cytarabine, pegaspargase or asparaginase, and filgrastim as in post-induction therapy B continuation I. Patients also receive oral lestaurtinib on days 2-6 in weeks 18, 22, 31, 35, and 44; days 6 and 7 in weeks 25 and 38; days 1-7 in weeks 26 and 39; days 1-6 in weeks 27 and 40; days 3-7 in weeks 28 and 41; and days 1-7 in weeks 29 and 42.
· Continuation II (weeks 48-104): Patients receive vincristine, dexamethasone, IT methotrexate, oral methotrexate, and oral mercaptopurine as in post-induction therapy B continuation II. Patients also receive lestaurtinib on days 2-6, 30-34, and 58-62. Treatment repeats every 12 weeks for 2 years from diagnosis.
Blood samples are collected periodically for pharmacokinetic studies and plasma inhibitory activity assay.
After completion of study treatment, all patients are followed every 1-6 months for 4 years and then annually thereafter.
Objectives
Primary
- To compare the 3-year event-free survival of infants with mixed lineage leukemia rearranged (MLL-R) acute lymphoblastic leukemia (ALL) randomized to treatment with a modified P9407 chemotherapy backbone with or without the FLT3 inhibitor lestaurtinib.
Secondary
- To determine a safe, tolerable, and biologically active dose of lestaurtinib given in sequential combination with chemotherapy in MLL-R infants.
- To characterize the pharmacokinetics and pharmacodynamics of lestaurtinib in infants when given at the proposed dose in sequential combination with chemotherapy.
- To identify molecular mechanisms of resistance to lestaurtinib in leukemic blasts.
- To describe levels of minimal residual disease in infants with ALL within the context of the proposed therapy, and correlate with outcome.
- To identify gene expression patterns in diagnostic infant leukemia samples that correlate with outcome within the context of the proposed therapy.
- To describe the outcome of infants with MLL-germline ALL treated with a modified P9407 chemotherapy backbone that includes an extended continuation phase.
Projected Accrual
A total of 244 patients will be accrued to this study.
Mechanism of Action
An orally bioavailable indolocarbazole derivative with antineoplastic properties. Lestaurtinib inhibits autophosphorylation of FMS-like tyrosine kinase 3 (FLT3), resulting in inhibition of FLT3 activity and induction of apoptosis in tumor cells that overexpress FLT3.
Entry Criteria
Disease Characteristics:
· Newly diagnosed acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia
· T-cell ALL allowed
· Bilineage or biphenotypic acute leukemia allowed provided the morphology and immunophenotype are predominately lymphoid
· Must be < 366 days of age at diagnosis; neonates in the first month of life must be > 36 weeks gestational age at diagnosis
· Must be enrolled on protocol COG-AALL03B1 prior to enrollment on this protocol
· Previously untreated except for the following:
· Steroid treatment within the past 48 hours allowed, provided that a physical examination and CBC with differential were performed immediately prior to beginning steroids
· Intrathecal (IT) chemotherapy (per protocol) is allowed for patient convenience at the time of the diagnostic bone marrow or venous line placement to avoid second lumbar puncture
· No B-cell ALL or acute myelogenous leukemia
Patient Characteristics:
Age
· Patients must be < 366 days of age at the time of diagnosis; for neonates in the first month of life, patients must be > 36 weeks gestational age at the time of diagnosis.
Other
· Patients with Down Syndrome are not eligible
Prior Concurrent Therapy:
· See Disease Characteristics
· No concurrent chronic steroid treatment for another disease
· No other concurrent non-protocol chemotherapy or investigational therapy
For more information, contact:
Rebecca Turner, MS, CCRP
Cincinnati Children’s Hospital Medical Center
Division of Hematology / Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2799
cancer@cchmc.org
